5-78034375-G-A

Variant names:

• chr5-78034375-G-A
• rs62001052
• NM_003664.5:c.2880C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.2880C>T​(p.Ala960Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,611,118 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (35 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.73
• Publications: 2 publications found

Genes affected

AP3B1 (HGNC:566): (adaptor related protein complex 3 subunit beta 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

AP3B1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.04).
• BP6: Variant 5-78034375-G-A is Benign according to our data. Variant chr5-78034375-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 354223.
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (572/152026) while in subpopulation NFE AF = 0.00419 (284/67844). AF 95% confidence interval is 0.00379. There are 11 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003664.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.2880C>T	p.Ala960Ala	synonymous	Exon 24 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2733C>T	p.Ala911Ala	synonymous	Exon 24 of 27	NP_001258698.1	O00203-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2880C>T	p.Ala960Ala	synonymous	Exon 24 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.2733C>T	p.Ala911Ala	synonymous	Exon 24 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.2880C>T	p.Ala960Ala	synonymous	Exon 24 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 572 AN: 151908 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00467 AC: 1172 AN: 251116 AF XY: 0.00456

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00370 AC: 5404 AN: 1459092 Hom.: 35 Cov.: 30 AF XY: 0.00353 AC XY: 2565 AN XY: 725990

African (AFR) AF: 0.000419 AC: 14 AN: 33402

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.0263 AC: 1404 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00344 AC: 3816 AN: 1109722

Other (OTH) AF: 0.00279 AC: 168 AN: 60286

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152026 Hom.: 11 Cov.: 32 AF XY: 0.00451 AC XY: 335 AN XY: 74320

African (AFR) AF: 0.000506 AC: 21 AN: 41510

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0247 AC: 262 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00419 AC: 284 AN: 67844

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.00369 Hom.: 2

Bravo AF: 0.00180

EpiCase AF: 0.00229

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hermansky-Pudlak syndrome 2 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62001052; hg19: chr5-77330199;